Excessive cholesterol (hyperlipoproteinemia) in the body leads to sclerosis (arteriosclerotic plaque) of the interior layers of the blood vessels, and to a gradual hardening and thickening of the arterial walls. In an extreme case, it threatens blocking of the vessels, or in the event of rupture of the plaque, thrombus formation. Arteriosclerosis with its secondary illnesses (coronary illnesses, heart attacks, peripheral arterial diseases and strokes) is still the most frequent cause of death in the western world. Well over half of all the financial resources available for medical care are estimated to be spent for the consequences of arteriosclerosis. To clarify the causes of arteriosclerosis, various theories have been developed, of which the lipid theory is the most highly regarded.
In general, it can be stated that the higher the LDL cholesterol level or level of oxidized LDL cholesterol in the blood, the high the risk of vascular hardening, for example with the consequence of a heart attack. Overweight and hypercholesterolemia are the most important risk factors for the development of arteriosclerosis.
Definitions and Terms
Fats such as cholesterol are soluble neither in water nor blood plasma. To allow them nevertheless to be transported to individual body regions, the fats are bound to particular albuminous substances (proteins) as soon as they occur in the blood. These compounds, comprising lipids (fats) and proteins, are termed lipoproteins.
The “lipoproteins” of the plasma are high-molecular weight water-soluble complex comprising lipids (cholesterol, triglycerides and phospholipids) and apolipoproteins. The cholesterol-containing lipoprotein LDL cholesterol causes arteriosclerosis and is also known as “bad” cholesterol, with the oxidized form of cholesterol being even more dangerous for the body.
“Cholesterol” is synthesized ubiquitously in the body and is an essential component of cell membranes and lipoproteins. In contrast to the triglycerides and phospholipids, which are also synthesized endogenously, the sterol ring of the cholesterol molecule can not be broken down again; cholesterol is transformed into bile acid in the liver or excreted unchanged with the bile into the gut.
In plasma, cholesterol is present as 25 to 40% free (non-esterified) cholesterol and 60 to 75% esterified with unsaturated fatty acids. Both forms together are known as the total cholesterol. Because of the low water solubility, cholesterol is transported in plasma as a complex with apolipoproteins. In the blood, about 70 percent of the total cholesterol is transported via low-density lipoproteins (LDL).
“Triglycerides” are esters of glycerine with three fatty acid residues. In the same way as cholesterol, the triglycerides are also transported in plasma bound to apolipoproteins because of their poor solubility.
“Lipoproteins” are synthesized in the liver or gut and transport liposoluble substances such as cholesterol in the blood.
Lipoproteins are classified according to their density into five density classes: chylomicrons, very low density lipoproteins (VDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). Chylomicrons, whose physiological concentration in fasting serum, unlike that of other lipoproteins, is very low, are vehicles for transporting exogenous glycerides. The physiological distribution of the other lipoproteins is as follows: VLDL 10%, LDL 70% and HDL 20%. VLDL are the precursors of LDL and vehicles for the transport of endogenous glycerides. LDL are produced by hydrolysis of VLDL. LDL and HDL are both regulators of cellular cholesterol homeostasis, with HDL also regulating lipolysis (splitting of triglycerides into glycerol and free fatty acids). LDL have a diameter of about 20 nm. HDL are the smallest (7-10 nm) and the most protein-rich lipoproteins. Besides native LDL (LDL), oxidized LDL (oxLDL) is also detectable in the blood serum oxLDL interacts with endogenous plasma proteins, particularly glycoproteins via specific ligands and forms oxLDL glycoprotein complexes.
“Apolipoproteins” are a component of lipoproteins and, together with polar lipids, as a kind of outer shell, surround the lipoprotein core, which is made up of hydrophobic lipids. With the exception of LDL, which only contains apoprotein B, the individual lipoprotein classes have a plurality of apolipoprotein classes with different structures.
Lipoprotein Transport
Cholesterol is principally transported via the two lipoprotein classes LDL and HDL. LDL are primarily responsible for cholesterol transport to peripheral cells that possess specific receptors for LDL. HDL permit and accelerate the removal of cholesterol from the extra-hepatic cells and vessel walls and transfer it to the livers.
Pathology
As regards the pathology of lipid metabolism disorders, it can be said in general that elevations in LDL cholesterol in conjunction with reductions in HDL cholesterol pose the most prominent increased risk of arteriosclerosis. In the pathogeny, LDL, whose particles make a substantial contribution to the formation of atherosclerotic plaques, and HDL therefore play contradictory roles. The quotients of total cholesterol/HDL cholesterol and, in particular, LDL cholesterol/HDL cholesterol are the deciding factors for assessing the risk of heart attack. (Epidemiological studies (Framingham study) also refer to the protective effect of HDL cholesterol.) The secondary diseases of arteriorsclerosis, besides coronary heart disease and peripheral arterial diseases, also include heart and brain infarcts (strokes).
oxLDL, just like LDL, probably causes arteriosclerotic plaques, with oxLDL posing the biggest danger for the body.
But oxLDL also appears to play an important role in other diseases. In patients with chronic kidney failure and diabetes, the concentration of oxLDL glycoprotein complexes is higher than in healthy patients.
LDL is also removed from the blood circulation by the liver and by macrophages. Macrophages are cells of the immune system, which are capable of phagocytosis of larger particles.
The “scavenger pathway” is a known model for explaining how cells engulf particles (phagocytosis). The incorporation of solid particles (debris, foreign bodies, bacteria or LDL plaques) into the cell interior of phagocytes, with subsequent intracellular breakdown, is carried out by phagocytosis. The phagocytic cells are known as phagocytes and consist predominantly of tissue macrophages and mobile blood monocytes.
In phagocytosis, after the particles become attached to the cell membranes of the phagocytes by binding to Fc and complement receptors on the membrane, contractile structures are activated within the cytoplasma. Local inversions of the cell membranes then cause inclusion of the particles in the cytoplasmic vacuoles.
So-called scavenger phagocytes are found in lymph nodes in and along the fibre strands that comprise the medulla.
Whereas the lymph passage from the afferent to the efferent end of the lymph node, particular antigens are removed by the phagocytic cells.
It is further known that the adherence to phagocytic cells, such as polymorphonuclear leucocytes and macrophages, is increased by the attachment of immunoglobulins (Ig) to the surface of bacteria (and other antigens). It is supposed that the increased adherence is effected by attachment of the Fc component of the immunoglobulin to the Fc receptors of the phagocytes. After the antigens have been made “appetizing” by the attachment of (or binding of) antibodies, the complex of antigen and antibodies is taken up and ingested faster by the phagocytic cells. The coating of the antibody surface with immunoglobulins is also known as opsonin-mediated (Fc) adherence, and plays an important role in the immune response.
The antibodies binding to the surface of bacterial cells are capable of fixing particular components of the extracellular liquids. In generic terms, these components are termed the “complement.” Animal tests have shown that the phagocytosis of cells coated with antibodies is delayed in animals lacking complement. It is thus obvious that opsonization involves a synergy between antibodies and complement.